Genetic Studies Uncover Clues to Childhood Brain Cancers ► NCI Cancer Bulletin for February 7, 2012 - National Cancer Institute

NCI Cancer Bulletin for February 7, 2012 - National Cancer Institute

Genetic Studies Uncover Clues to Childhood Brain Cancers

Two genetic studies of brain tumors in children have identified a new suspect in these deadly cancers. In each study, researchers found recurrent mutations in a protein that helps package DNA in the cell nucleus.

Changes to this process may alter the activity of genes and contribute to cancer, the researchers reported.
In one study, published online January 29 in Nature, researchers sequenced the entire exome (all protein-coding DNA) of tumors from 48 children with glioblastoma multiforme (GBM), an aggressive form of brain cancer. The sequencing revealed two recurrent mutations in a gene called H3F3A, which encodes a histone protein (H3.3).

Histones assemble into structures called nucleosomes, around which long strands of DNA wrap, resulting in a tightly packaged complex called chromatin. Because histones interact so closely with DNA, structural modifications to histone proteins can also control gene activity.

Two recent studies (here and here) have found evidence that mutations in genes whose products modify histones may be involved in cancer. The Nature study, however, is the first to describe mutations in a histone gene in tumors. “Histones are, in a way, the guardians of our genetic information,” said Dr. Nada Jabado of McGill University, who led the research.

She and her colleagues also found that some GBM tumors had mutations in genes that are involved in chromatin remodeling, a process in which chromatin “opens” so that transcription factors can gain access to DNA, allowing previously silent genes to be transcribed. Defects in the chromatin remodeling pathway may be common in pediatric GBM and could be the basis for exploring much-needed new treatments for the disease, the study authors concluded.

“We now have a starting point for investigating the biological basis of this disease,” Dr. Jabado continued. “Until now, we essentially have been working in the dark.”

In a separate study, researchers with the Pediatric Cancer Genome Project also found the same mutations in H3F3A or a closely related gene, HIST1H3B, in 78 percent of tumors from 50 children with a cancer known as diffuse intrinsic pontine glioma (DIPG). The findings were reported online in Nature Genetics on January 29.

“It’s not often that you find a mutation that affects such a high proportion of [patient samples],” said senior author Dr. Suzanne Baker of St. Jude Children’s Research Hospital. “This tells us that anything we learn about this mutation will reveal something important about the biology of this disease.”

The finding also adds weight to the idea that epigenetic processes are being undermined in some cancers, Dr. Baker added. “I expect that significant resources will now be devoted to understanding how and why alterations in the histone proteins contribute to cancer.”